Milk for Diabetes Prevention

Overview

Individuals with lactase non-persistence (LNP; determined by a functional variant in the LCT gene \[rs4988235, GG genotype\]) are susceptible to lactose intolerance in adulthood due to deficiency of lactase, the enzyme which digests milk lactose sugars. However, many LNP individuals still drink ≥1 cup of milk daily. Recent analysis in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) found that consumption of 1 serving (cup) of milk/day was associated with \~30% lower risk of type 2 diabetes among LNP individuals, but not among individuals with lactase persistence (LP). This beneficial effect might be partially explained by favorable alterations in gut microbiota and related metabolites associated with higher milk consumption among LNP individuals. Based on these observational study findings, the investigator team proposes to conduct a randomized, controlled trial of lactose-containing vs. lactose-free milk in LNP individuals with pre-diabetes, to comprehensively investigate the effects of milk intake on the gut microbiome and glycemic outcomes.

Detailed description

The trial will feature a 2-week milk washout period, followed by 1:1 randomization to lactose-containing (1% or 2%) or lactose-free (1% or 2%) milk for 12 weeks (4 weeks each of ½ cup, 1 cup, and 2 cups milk). Before and after the 12 weeks, visits will entail lactose challenge hydrogen breath tests (HBT; i.e., lactose tolerance tests) and blood tests for fasting glucose, hemoglobin A1c, and metabolomics; while stool samples and continuous glucose monitoring (CGM) data will be collected at home using provided kits/devices.

Specific aims of the study are to: (1) establish feasibility and tolerability of a randomized trial of lactose-containing vs. lactose-free milk; (2) to examine the effect of lactose-containing milk on gut microbiome species, functions, and metabolites in LNP individuals with pre-diabetes; and (3) to examine the effect of lactose-containing milk on glycemic outcomes in LNP individuals with pre-diabetes.

Interventions

• Dietary supplement Lactose-Containing Milk
  Participants will be asked to drink regular milk (1% or 2%) for 12 weeks as follows: * Weeks 1-4: ½ cup milk per day * Weeks 5-8: 1 cup milk per day * Weeks 9-12: 2 cups milk per day Participants will continue drinking 2 cups milk/day for 2 weeks after the 12-week follow-up visit.
• Dietary supplement Lactose-Free Milk
  Participants will be asked to drink 1% or 2% lactose-free milk for 12 weeks as follows: * Weeks 1-4: ½ cup milk per day * Weeks 5-8: 1 cup milk per day * Weeks 9-12: 2 cups milk per day Participants will continue drinking 2 cups milk/day for 2 weeks after the 12-week follow-up visit.

Primary outcome measures

• Gastrointestinal symptoms [Time frame: Daily From Screening visit to Week 12]
• Change in Expired Breath Hydrogen [Time frame: From Baseline to Week 12]
• Change in gut microbiome features - Relative Abundance of Species [Time frame: From Baseline to Week 12]
• Change in gut microbiome features - Functional Pathway Relative Abundance [Time frame: From Baseline to Week 12]
• Change in gut microbiome features - Metabolomics [Time frame: From Baseline to Week 12]
• Change in glycemic outcomes - Fasting glucose [Time frame: From Baseline to Week 12]
• Change in glycemic outcomes - Hemoglobin A1c (HbA1c) [Time frame: From Baseline to Week 12]
• Change in glycemic outcomes - Continuous Glucose Monitoring (CGM) mean glucose [Time frame: From Screening visit to Week 14 visit]
• Change in glycemic outcomes - Continuous Glucose Monitoring (CGM) glycemic variability [Time frame: From Screening visit to Week 14 visit]
• Change in glycemic outcomes - Continuous Glucose Monitoring (CGM) time above range [Time frame: From Screening visit to Week 14 visit]

Eligibility criteria

Inclusion criteria

• LNP genotype (LCT gene rs4988235, GG genotype)
• History of pre-diabetes, defined as fasting blood glucose 100-125 mg/dL and/or hemoglobin A1c (HbA1c) 5.7-6.4% and have not been diagnosed with diabetes nor take diabetes medication (pre-diabetes determined at most recent study visit \[for HCHS/SOL participant\] or most recent medical chart or self-report \[for other participant\])
• Drink ≤1 cup milk/day
• Basic computer or smartphone skills
• Can speak and read English fluently

Exclusion criteria

• Diabetes diagnosis
• Taking anti-diabetes medication
• Cancer, cardiovascular disease (CVD), or life-threatening illness
• Known milk allergy
• Has severe GI symptoms after drinking milk
• History of GI surgery
• Had a double mastectomy
• Smoking
• More than 1 alcoholic beverage/day
• Pregnant or breastfeeding
• Colonoscopy in last 2 weeks
• Antibiotics in last 3 months
• Taking probiotics or fiber supplements (if taking, must be able to stop taking during study)
• Taking laxatives, stool softeners, anti-diarrheal (if taking, must be able to stop taking during study)
• Taking lactase pills (if taking, must be able to stop taking)
• Participating in extreme dieting program
• Planning extended travel that would prevent participation in study
• Taking medication that must be taken separate from calcium or dairy products

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Prevention

Study locations

United States · 1 center

• HCHS/SOL Bronx Field Center — The Bronx

Publications

• Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, Shaw JE, Bright D, Williams R; IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019 Nov;157:107843. do PMID 31518657
• GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020 Oct 17;396(10258):1204-1222. doi: 10.1016/S0140-6736(20)30925-9. PMID 33069326
• Parker ED, Lin J, Mahoney T, Ume N, Yang G, Gabbay RA, ElSayed NA, Bannuru RR. Economic Costs of Diabetes in the U.S. in 2022. Diabetes Care. 2024 Jan 1;47(1):26-43. doi: 10.2337/dci23-0085. PMID 37909353
• Uusitupa M, Khan TA, Viguiliouk E, Kahleova H, Rivellese AA, Hermansen K, Pfeiffer A, Thanopoulou A, Salas-Salvado J, Schwab U, Sievenpiper JL. Prevention of Type 2 Diabetes by Lifestyle Changes: A Systematic Review and Meta-Analysis. Nutrients. 2019 Nov 1;11(11):2611. doi: 10.3390/nu11112611. PMID 31683759
• Wareham NJ. Personalised prevention of type 2 diabetes. Diabetologia. 2022 Nov;65(11):1796-1803. doi: 10.1007/s00125-022-05774-7. Epub 2022 Aug 2. PMID 35916901
• Liu B, Sun Y, Bao W. Creating and supporting a healthy food environment for type 2 diabetes prevention. Lancet Planet Health. 2018 Oct;2(10):e423-e424. doi: 10.1016/S2542-5196(18)30211-0. No abstract available. PMID 30318098
• Aune D, Norat T, Romundstad P, Vatten LJ. Dairy products and the risk of type 2 diabetes: a systematic review and dose-response meta-analysis of cohort studies. Am J Clin Nutr. 2013 Oct;98(4):1066-83. doi: 10.3945/ajcn.113.059030. Epub 2013 Aug 14. PMID 23945722
• Luo K, Chen GC, Zhang Y, Moon JY, Xing J, Peters BA, Usyk M, Wang Z, Hu G, Li J, Selvin E, Rebholz CM, Wang T, Isasi CR, Yu B, Knight R, Boerwinkle E, Burk RD, Kaplan RC, Qi Q. Variant of the lactase LCT gene explains association between milk intake and incident type 2 diabetes. Nat Metab. 2024 Jan;6(1):169-186. doi: 10.1038/s42255-023-00961-1. Epub 2024 Jan 22. PMID 38253929

Identifiers

NCT: NCT06513026 · 2024-16045

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗